JP3171279B2 - Method for producing alkylphosphocholine having 14 to 18 carbon atoms and method for purifying alkylphosphocholine - Google Patents

Abstract

Process for the preparation of C14-C18-alkylphosphocholines in a one-pot process by reaction of an n-alkanol having a chain length of C14-C18 with phosphorus oxychloride in an inert solvent or else without solvent in the presence or absence of a basic substance, and further reaction of the reaction product in an inert solvent with a choline salt in the presence of a basic substance to give the phosphoric acid diester chloride, followed by hydrolysis and isolation of alkylphosphocholine, and, if appropriate, purification by means of a mixed-bed ion exchanger or in succession with an acidic ion exchanger and a basic ion exchanger.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates, C ₁₄ ~C ₁₈ - relates to the purification method of preparation and alkylphosphocholines of alkylphosphocholines.

[0002]

2. Description of the Related Art Eibl et al .;
EP 225608 describes the production of alkylphosphocholines and their use for treating tumors. The Ible process uses n-alcohol and phosphorus oxychloride as starting materials. These are reacted in tetrahydrofuran to give phosphoric acid ester dichloride. In the second step, 2-aminoethanol is reacted with phosphoric acid ester dichloride in dioxane to give 2-hexadecyl-1,3,2-oxaphosphorane-2-oxide. Hydrolysis with 2N hydrochloric acid gives the open-chain amine, which is exhaustively methylated in 2-propanol with dimethyl sulfate to alkyl phosphocholine.

[0003] This method has the following disadvantages: It is necessary to isolate and purify the intermediate. Further, an alkylating reagent is used. The use of potassium carbonate as an auxiliary base during this reaction step results in a high potassium content in the product which is undesirable for pharmaceutical purposes.

[0004] Long-chain alkylphosphocholines having a bactericidal action have been described by Kanetani et al. In Kanetani et al., Nipp.
onKayaku Kaishi), 9, 1452 (1
984). These are prepared by the following method: ethylene glycol and phosphorus trichloride are reacted to give 2-chloro-1,3,2-dioxaphospholane, and the product purified by distillation is oxidized with oxygen to give −
Chlor-1,3,2-dioxaphosphorane-2-oxide is formed and subsequently distilled again. 2-chloro-1,3,3
2-dioxaphosphorane-2-oxide followed by 1
-2-hexadecyl reacted with hexadecanol-
1,3,2-dioxaphosphorane-2-oxide. 2-Hexadecyl-1,3,2-dioxaphosphorane-2-oxide is reacted with trimethylamine in an autoclave to give hexadecylphosphocholine, and the crude product is purified on alkaline and acidic ion exchangers and acetone / Recrystallize from chloroform. A similar method is useful for the preparation of octyl, decyl, dodecyl, tetradecyl, octadecyl derivatives.

[0005] This process has to be carried out at high pressure in the last reaction step, and the use of trimethylamine has the disadvantage that it causes industrial hygiene problems in the industrial production of the substance. Further, the intermediates 2-chloro-1,3,2-dioxaphosphorane, 2-chloro-1,
It is disadvantageous that 3,2-dioxaphospholane-2-oxide and 2-hexadecyl-2-oxa-1,3,2-dioxaphospholane must be isolated and purified. Furthermore, a solvent with an environmental load, for example, benzene, is used, in which case the solvent is changed every step.

All known methods use chromatographic methods for working up and purifying the crude product.

[0007] However, such chromatographic work-up methods have the following disadvantages:-Their conversion to industry standards is difficult. This is because the dimensions of the stationary phase cannot be increased as much as possible.

[0008] The chromatographic method is time-consuming.

[0009]

The present invention relates to a new and advantageous process for the preparation of alkylphosphocholines and to a work-up process.

[0010]

SUMMARY OF THE INVENTION Surprisingly, despite the fact that purification steps are used less than previously known methods,
It has been found that a higher overall yield is obtained with the method of the invention. Furthermore, according to the invention, less solvent is used. The process according to the invention also avoids the use of alkylating reagents, such as dimethyl sulphate, which lead to a high potassium content of the product by using potassium carbonate as auxiliary base. In the case of substances used as pharmaceutically active substances, the potassium content should be as low as possible.

The process according to the invention avoids the time-consuming chromatographic steps in the work-up.

The product units obtained in the claimed process are:
Higher than that obtained by known methods.

[0013] The first step of the reaction comprises a halogenated hydrocarbon,
Cyclic saturated ether, acyclic ether, C-atom 5-10
Saturated hydrocarbons, liquid aromatic hydrocarbons which may be replaced by halogens (especially chlorine) or the presence of basic substances which are customary for this purpose in solvents-free mixtures or with or without solvents Below, reacting phosphorus oxychloride with an n-alkanol having a chain length of 14 to 18 carbon atoms.

As the halogenated hydrocarbon, for example, C-
Hydrocarbons consisting of 1 to 6 atoms correspond to this, wherein one or more or all of the hydrogen atoms are replaced by chlorine atoms. For example, methylene chloride, chloroform, ethylene chloride, chlorobenzene, dichlorobenzene can be used. If halogen-substituted aromatic hydrocarbons are used, they are advantageously substituted with one or two halogen atoms.

As the cyclic unsaturated ether, for example, an ether having one or two carbon atoms and one or two oxygen atoms and having 5 to 6 ring members can be used. Examples of this are tetrahydrofuran and dioxane.

Acyclic ethers are composed of 2 to 8 carbon atoms and are liquids. For example, diethyl ether, diisobutyl ether, methyl-t-butyl ether, and diisopropyl ether correspond to this.

As the saturated hydrocarbon, 5 to 10 carbon atoms are used.
This is the case for unbranched or branched hydrocarbons which are made up of solids and are liquid. For example, pentane, hexane, heptane and cyclohexane correspond to this.

The aromatic hydrocarbons include, for example, benzene and alkyl-substituted benzenes, wherein the alkyl substituent consists of 1 to 5 carbon atoms.

As basic substances for the reaction of phosphorus oxychloride with n-alkanols and the subsequent reaction with choline salts, amines such as, for example, formulas NR ₁ R ₂ R ₃ , wherein
R ₁ , R ₂ and R ₃ are the same or different and represent hydrogen or C ₁ -C ₆ -alkyl], aliphatic amines, aromatic amines such as pyridine, picoline, quinoline . In the reaction with the choline salt, the basic substance required here can be added simultaneously with or before the choline salt. Regarding the reaction with choline salt,
In each case a solvent is required; that is, if the first reaction step is carried out without special solvents, such must be added there. The molar ratio of phosphorus oxychloride to alkanol is, for example, from 1.5: 1 to 1: 1.1.

The choline salt is used in excess, for example, relative to the alkanol (about 1.1 to 1.5 molar excess). When the reaction between phosphorus oxychloride and an alkanol is performed in the presence of a basic substance, the amount of the basic substance is, for example, POCl ₃ 1
It is 1 to 3 moles per mole. For the subsequent reaction with the choline salt, the amount of basic substance used is, for example, 1 to 5 mol per mol of alkanol.

The reaction temperature of the reaction between phosphorus oxychloride and n-alkanol is from -30.degree. C. to + 30.degree. C., preferably -15.degree.
To + 5 ° C, especially -10 ° C to -5 ° C.

The reaction time of this reaction is, for example, 0.5 to 5
Hours, preferably 1 to 3 hours, especially 1.5 to 2 hours.
When the reaction is performed in the presence of a basic substance, the reaction generally proceeds rapidly (about 30 minutes).

Thereafter, the choline salt is added in a small amount or completely. Salts of choline include salts with mineral acids (for example, sulfuric acid and hydrochloric acid), and salts of choline with organic acids such as acetic acid and p-toluenesulfonic acid.

This reaction step is performed in an inert solvent. If this reaction is carried out in a solvent, here the same solvents as used for the reaction of phosphorus oxychloride with n-alkanols apply.

The basic substance is subsequently dissolved in one of the solvents mentioned or added dropwise without solvent. Here, preference is given to using as solvents for basic substances: halogenated hydrocarbons, cyclic saturated ethers, acyclic ethers, saturated hydrocarbons having 5 to 10 carbon atoms, liquid aromatics Group hydrocarbons or mixtures from the abovementioned solvents. here,
This is the same solvent that can be used for the reaction of phosphorus oxychloride with n-alkanols.

The temperature rises due to the addition of the basic substance.
The temperature is between 0.degree. C. and 40.degree. C., preferably between 10.degree.
Care is taken to keep the temperature between 5 ° C and 20 ° C.

The reaction mixture is then heated at 5 ° C. to 30 ° C., preferably at 15 ° C. to 25 ° C. (for example for 1 to 40 hours, preferably 3 to
(15 hours) Further stirring.

The hydrolysis of the reaction batch is carried out by adding water, the temperature being from 10 ° C. to 30 ° C., preferably from 15 ° C. to 3 ° C.
It should be kept at 0 ° C, especially between 15 ° C and 20 ° C.

[0029] The hydrolyzate may also contain a basic substance. Such basic substances include alkali metal and alkaline earth metal carbonates and bicarbonates.

In order to complete the hydrolysis,
0 ° C to 30 ° C, preferably 15 ° C to 25 ° C, especially 18 ° C to 2 ° C
At 2 ° C., for 0.5 to 4 hours, preferably 1 to 3 hours, in particular 1.
Stir further for 5-2.5 hours.

The reaction mixture is then washed with a mixture of water and an alcohol (preferably an aliphatic saturated alcohol having 1 to 4 carbon atoms), optionally containing basic substances. The mixing ratio of water: alcohol is, for example, 5 to 5.
0.5, preferably 1 to 3 (V / V).

The basic substances for the washing liquid include, for example, alkali metals and alkaline earth metals in the form of aqueous solutions, and carbonates and bicarbonates of ammonia.
Particular preference is given to washing the reaction solution with a 3% aqueous sodium carbonate solution, optionally followed by an acid solution. Particularly when using methylene chloride as a solvent, acid washing to remove unreacted basic components of the reaction solution is advantageous.

The cleaning liquid consists of a mixture of water and alcohol. Preference is given to mixtures of aliphatic saturated alcohols having 1 to 4 carbon atoms, in which case acidic substances may be present. The mixing ratio of water: alcohol is, for example, 5 to 0.5, preferably 1 to 3 (V
/ V).

Acidic substances for the washing liquid include, for example, mineral acids and organic acids, such as hydrochloric acid, sulfuric acid or tartaric acid and citric acid.

A 10% aqueous solution of hydrochloric acid is particularly advantageous.

Subsequently, it is washed once more with a mixture of water and alcohol. Preference is given to mixtures from aliphatic saturated alcohols having 1 to 4 carbon atoms,
At that time, a basic substance may be present in some cases.
The mixing ratio of water: alcohol may for example be 5 to 0.5, preferably 1 to 3.

The washing layers are then collected and dried in a conventional manner,
The solvent is then removed (preferably under reduced pressure, for example from 5 to 100 mbar), optionally from 1.5 to 3 aliphatic alcohols.
l, preferably 2 to 2.5 l (based on 1 part by weight of dry product), are removed. Alcohols which preferably are aliphatic saturated alcohols having a chain length of 1 to 5 carbon atoms preferably correspond to this. Particularly preferred alcohols here are n-butanol and isopropanol. This alcohol treatment aims at complete removal of residual water.

The product thus obtained can be purified by customary methods (for example by chromatography, recrystallization).

The alkylphosphocholine crude product or the solid residue is, for example, an aliphatic saturated ketone (3 carbon atoms).
-6), for example, suspended in acetone, butanone, methyl tert-butyl ketone, stirred for 1-4 hours, preferably 2 hours, filtered off with suction and dried in vacuo at 5-100 Torr at 20
Dry at 50C to 50C.

However, the following purification method according to the invention is particularly advantageous.

The product thus pre-purified is dissolved in anhydrous alcohol (C ₁ -C ₄ ) or an alcohol containing up to 5% by weight of water at 20 ° C. to 60 ° C., preferably 4 ° C.
Take at 0 ° C. and filter off insolubles. As alcohol,
For example, methanol, ethanol, isopropanol, butanol, and isobutanol are used. Further, the pre-purified product may be dissolved in water. The obtained filtrate is then mixed with a mixed bed ion exchanger such as Amberlite (Amlite).
berlite: registered trademark; hereinafter omitted) along with MB3,
For example, at 10 ° C to 50 ° C, preferably at 20 ° C, for 1 to 5 hours,
Stir preferably for 2 hours. Purification can also be performed using an acidic ion exchanger and a basic ion exchanger simultaneously or successively instead of the mixed-bed ion exchanger.

As the ion exchanger, any insoluble solid containing an ion exchange group can be used.

The acidic ion exchanger contains, for example, an acid group, for example, a sulfonic acid group or a carboxyl group. Examples are ion exchangers having sulfonic acid groups in a polystyrene matrix, such as Amberlite IR12
0, Dowex (registered trademark; omitted hereafter) H
CR, Duolite (registered trademark; hereinafter omitted) C20 or Lewatit (registered trademark; hereinafter omitted) S100. Weakly acidic ion exchangers are for example based on polyacrylic acid-matrix,
Those having a carboxylic acid group, such as Amberlite IRC76, Duolite C433 or Relite (R
elite: registered trademark; omitted hereafter) CC.

Examples of the basic ion exchanger include those having a primary, secondary, tertiary or quaternary amino group in a polymer matrix (for example, polystyrene matrix), for example, Duolite A101 and Duolite A10.
2, Duolight 15A348, Duolight A36
5, Duolite A375, Amberlite IRA6
7, Duolite A375, Amberlite IRA45
8 and Duolight A132 correspond to this.

The mixed bed type ion exchanger is a mixture of acidic and alkaline ion exchanger resins, for example, Amberlite MB1, Amberlite MB2, Amberlite M
B3 and Amberlite MB6.

Further, commercially available all ion exchangers can be used in this method.

In other respects, Ullman's Encyclopedia of Industrial Chemistry (U.
llmann's Encyclopedia of
Industrial Chemistry), 5th edition (1989), volume A14, page 450.

After the ion exchange resin has been filtered off with suction, it is evaporated under reduced pressure (eg 20-200 Torr) at 40 ° C. to 70 ° C. and subsequently recrystallized from a halogenated hydrocarbon or alcohol / ketone mixture. Let it.

The halogenated hydrocarbon for recrystallization includes
For example, hydrocarbons from 1 to 6 C-atoms correspond, in which case one or more or all of the hydrogen atoms are replaced by chlorine atoms. For example, methylene chloride, chloroform, ethylene chloride, chlorobenzene may be used.

The alcohol corresponds to an aliphatic saturated alcohol having 1 to 6 carbon atoms and 1 to 2 hydroxyl groups. Ketones include 3 to 8 carbon atoms
This is the case for aliphatic saturated ketones having a single bond.

The mixing ratio of alcohol to ketone is 1: 1 to 1
5 (capacity / capacity). An ethanol / acetone mixture in a 1: 1 ratio (V / V) is particularly advantageous.

The obtained crystals of alkylphosphocholine are:
Suction filtration and washing with a saturated hydrocarbon having, for example, 1 to 6 carbon atoms (the temperature of the washing solution is, for example, 15 to 30 ° C.)
Is).

Drying is carried out, for example, on a conventional drying agent such as phosphorus pentoxide or silica gel at 40-80 ° C. in vacuo.

[0054]

【Example】

Example 1 Preparation of hexadecyl-phosphocholine In a 6 l-stirring apparatus, under nitrogen, 1.0 mol (92 ml) of POCl ₃ are introduced into 1.5 l of chloroform and cooled to 5 ° C. in an ice bath. 0.90 mol of hexadecanol
(218 g) are dissolved in 700 ml of chloroform and added dropwise with 4.00 mol (320 ml) of pyridine at a temperature of 5-12 ° C. Addition time: 1.25 hours. The addition funnel is post-washed with the remaining 300 ml of chloroform. 0-5 ° C
After stirring for one and a half hours, solid choline tosylate 1.
35 mol (372 g) are added, followed by pyridine 40
0 ml is added dropwise over 15 minutes. At that time, the temperature is 2
Increase to 0 ° C. The ice bath is removed and the reaction mixture is stirred at room temperature for 3 hours. 20 ml of 150 ml of water for hydrolysis
Dropwise over a period of 25 minutes, the temperature being
Increase to ° C. After stirring for half an hour, each time the reaction solution was mixed with 1.50 l of water / methanol (1: 1), 1.50 l of 3% sodium carbonate / methanol (1: 1) and 1.50 l of water / methanol (1: 9). Wash with. The chloroform phase so washed is dried over sodium sulfate,
Spin in vacuo after addition of 50 ml of i-propanol. For drying, add n-butanol and spin again.

The purification is carried out in the following way: the residue is suspended in 2.0 l of acetone, stirred for about 2 hours, filtered off with suction,
Dry at 30 ° C. in vacuo. Crude yield: 325 g (87
%). The crude product is taken up in 3.0 l of absolute ethanol and the insolubles are filtered off. The filtrate is stirred for 2 hours with 1.0 l of mixed bed-ion exchanger Amberlite MB3 (FLUKA). After filtering off the ion exchange resin with suction, it is spun in vacuo and subsequently recrystallized once from 0.70 l of methylene chloride. Complete crystallization is achieved in the refrigerator. The crystals are filtered off with suction and washed with pentane. Dry over phosphorous pentoxide at 30 ° C. in vacuo.

Yield: 193 g (0.47 mol, 53%) The reaction product has a melting point of 241 ° -245 ° C.

Examples 2 to 5 were produced in the same manner.

Example 2:

[0059]

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Example 3:

[0061]

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Example 4:

[0063]

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Example 5:

[0065]

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──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Wolfgang Schumacher Germany Germany Langen Theodor Le Hois-Strasse 37 (72) Inventor Wolf Niemeyer Germany Offenbach Berliner Straße 236 (72) Inventor Alfred Olbrich Germany Ober Zhausen Munchner Strasse 1 (72) Inventor Gerhard Nesner Offenbach Odenwaldring, Germany 7 (56) References JP-A-62-16497 (JP, A) JP-A-58-46062 (JP, A) JP-A Sho 58 57-118556 (JP, A) JP-A-58-144333 (JP, A) JP-A-56-156256 (JP, A) JP-A 50-83323 (JP, A) (58) The field (Int.Cl. ^7, DB name) C07F 9/09 CA (STN)

Claims (3)

(57) [Claims] 1. A n- alkanols and oxy C ₁₄ -C by reaction with phosphorus chloride, and choline salts ₁₈ - in making the alkyl phosphocholine, chain length in the one-shot method C ₁₄ -C ₁₈
Is reacted with an n-alkanol having the formula (I) and phosphorus oxychloride in an inert solvent or without a solvent in the presence or absence of a basic substance, and without the isolation and purification of the obtained product, in a solvent, in the presence of a basic substance is further reacted with a choline salt in the phosphoric acid diester chloride, characterized by isolating liberate alkylphosphocholines by subsequent hydrolysis, C ₁₄ -C ₁₈ - alkyl Formula for phosphocholine. 2. A reaction with a choline salt in the presence of a basic substance.
The process according to claim 1, wherein the reaction is carried out at a reaction temperature of 0 to 40 ° C.
Law . 3. A method for purifying alkyl phosphocholine, a 請 Motomeko 1 or 2 alkylphosphocholines of solutions prepared by the method described, an organic agent or in the water,
A method for purifying an alkylphosphocholine, which comprises treating with a mixed bed ion exchanger or, in order, with an acidic ion exchanger and a basic ion exchanger.